title: Notch1 is required in newly postmitotic cells to inhibit the rod photoreceptor fate.
abstract: Several models of cell fate determination can be invoked to explain how single retinal progenitor cells (RPCs) produce different cell types in a terminal division. To gain insight into this process, the effects of the removal of a cell fate regulator, Notch1, were studied in newly postmitotic cells using a conditional allele of Notch1 (N1-CKO) in mice. Almost all newly postmitotic N1-CKO cells became rod photoreceptors, whereas wild-type (WT) cells achieved a variety of fates. Single cell profiling of wild-type and N1-CKO retinal cells transitioning from progenitor to differentiated states revealed differential expression of inhibitor of DNA binding factors Id1 and Id3, as well as Notch-regulated ankyrin repeat protein (Nrarp). Misexpression of Id1 and Id3 was found to be sufficient to drive production of Müller glial cells and/or RPCs. Moreover, Id1 and Id3 were shown to partially rescue the production of bipolar and Müller glial cells in the absence of Notch1 in mitotic and newly postmitotic cells. Misexpression of Nrarp, a downstream target gene and inhibitor of the Notch signaling pathway, resulted in the overproduction of rod photoreceptors at the expense of Müller glial cells. These data demonstrate that cell fate decisions can be made in newly postmitotic retinal cells, and reveal some of the regulators downstream of Notch1 that influence the choice of rod and non-rod fates. Taken together, our results begin to address how different signals downstream from a common pathway lead to different fate outcomes.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Karolina
authors.initials: K
authors.lastname: Mizeracka
authors.forename: Christina R
authors.initials: CR
authors.lastname: DeMaso
authors.forename: Constance L
authors.initials: CL
authors.lastname: Cepko
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques / Q000379:methods; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D008954:Models, Biological; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D051796:Inhibitor of Differentiation Proteins; D047908:Intracellular Signaling Peptides and Proteins; C497762:Notch1 protein, mouse; C499040:Nrarp protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; C067679:Idb3 protein, mouse
keywords: Cell fate; Id; Mouse; Notch; Nrarp; Postmitotic; Retina